Evaluation of Autoantibody Binding to Cardiac Tissue in Multisystem Inflammatory Syndrome in Children and COVID-19 Vaccination–Induced Myocarditis
Authors: Harsita Patel, Amalia Sintou, Rasheda A. Chowdhury, Stephen Rothery, Alma Octavia Iacob, Sanjay Prasad, Peter P. Rainer, Federico Martinón-Torres, Vanessa Sancho-Shimizu, Chisato Shimizu, Kirsten Dummer, Adriana H. Tremoulet, Jane C. Burns, Susanne Sattler, Michael Levin, Aubrey Cunnington, Jethro Herberg, Myrsini Kaforou, Victoria J. Wright, Evangelos Bellos, Claire Broderick, Samuel Channon-Wells, Samantha Cooray, Tisham De, Giselle D’Souza, Leire Estramiana Elorrieta, Diego Estrada-Rivadeneyra, Rachel Galassini, Dominic Habgood-Coote, Shea Hamilton, Heather Jackson, James Kavanagh, Ilana Keren, Mahdi Moradi Marjaneh, Stephanie Menikou, Samuel Nichols, Ruud Nijman, Ivana Pennisi, Oliver Powell, Ruth Reid, Priyen Shah, Ortensia Vito, Elizabeth Whittaker, Clare Wilson, Rebecca Womersley, Amina Abdulla, Sarah Darnell, Sobia Mustafa, Pantelis Georgiou, Jesus-Rodriguez Manzano, Nicolas Moser, Michael Carter, Shane Tibby, Jonathan Cohen, Francesca Davis, Julia Kenny, Paul Wellman, Marie White, Matthew Fish, Aislinn Jennings, Manu Shankar-Hari, Katy Fidler, Dan Agranoff, Vivien Richmond, Mathhew Seal, Saul Faust, Dan Owen, Ruth Ensom, Sarah McKay, Mariya Shaji, Rachel Schranz, Prita Rughnani, Amutha Anpananthar, Susan Liebeschuetz, Anna Riddell, Divya Divakaran, Louise Han, Nosheen Khalid, Ivone Lancoma Malcolm, Jessica Schofield, Teresa Simagan, Mark Peters, Alasdair Bamford, Lauran O’Neill, Nazima Pathan, Esther Daubney, Deborah White, Melissa Heightman, Sarah Eisen, Terry Segal, Lucy Wellings, Simon B Drysdale, Nicole Branch, Lisa Hamzah, Heather Jarman, Maggie Nyirenda, Lisa Capozzi, Emma Gardiner, Robert Moots, Magda Nasher, Anita Hanson, Michelle Linforth, Sean O’Riordan, Donna Ellis, Akash Deep, Ivan Caro, Fiona Shackley, Arianna Bellini, Stuart Gormley, Samira Neshat, Barnaby Scholefield, Ceri Robbins, Helen Winmill, Stéphane C Paulus, Andrew J Pollard, Mark Anthony, Sarah Hopton, Danielle Miller, Zoe Oliver, Sally Beer, Bryony Ward, Shrijana Shrestha, Meeru Gurung, Puja Amatya, Bhishma Pokhrel, Sanjeev Man Bijukchhe, Madhav Chandra Gautam, Sarah Kelly, Peter O’Reilly, Sonu Shrestha, Federico Martinón-Torres, Antonio Salas, Fernando Álvez González, Sonia Ares Gómez, Xabier Bello, Mirian Ben García, Fernando Caamaño Viña, Sandra Carnota, María José Curras-Tuala, Ana Dacosta Urbieta, Carlos Durán Suárez, Isabel Ferreiros Vidal, Luisa García Vicente, Alberto Gómez-Carballa, Jose Gómez Rial, Pilar Leboráns Iglesias, Narmeen Mallah, Nazareth Martinón-Torres, José María Martinón, Belén Mosquera Pérez Sánchez, Jacobo Pardo-Seco, Sara Pischedda, Sara Rey Vázquez, Irene Rivero Calle, Carmen Rodríguez-Tenreiro, Lorenzo Redondo-Collazo, Sonia Serén Fernández, Marisol Vilas Iglesias, Enitan D Carrol, Elizabeth Cocklin, Rebecca Beckley, Abbey Bracken, Ceri Evans, Aakash Khanijau, Rebecca Lenihan, Nadia Lewis-Burke, Karen Newall, Sam Romaine, Jennifer Whitbread, Maria Tsolia, Irini Eleftheriou, Nikos Spyridis, Maria Tambouratzi, Despoina Maritsi, Antonios Marmarinos, Marietta Xagorari, Lourida Panagiota, Pefanis Aggelos, Akinosoglou Karolina, Gogos Charalambos, Maragos Markos, Voulgarelis Michalis, Stergiou Ioanna, Marieke Emonts, Emma Lim, John Isaacs, Kathryn Bell, Stephen Crulley, Daniel Fabian, Evelyn Thomson, Diane Wallia, Caroline Miller, Ashley Bell, Fabian J S van der Velden, Geoff Shenton, Ashley Price, Owen Treloar, Daisy Thomas, Pablo Rojo, Cristina Epalza, Serena Villaverde, Sonia Márquez, Manuel Gijón, Fátima Machín, Laura Cabello, Irene Hernández, Lourdes Gutiérrez, Ángela Manzanares, Taco W Kuijpers, Martijn van de Kuip, Marceline van Furth, Merlijn van den Berg, Giske Biesbroek, Floris Verkuil, Carlijn van der Zee, Dasja Pajkrt, Michael Boele van Hensbroek, Dieneke Schonenberg, Mariken Gruppen, Sietse Nagelkerke, MachielH Jansen, Ines Goetschalckx, Lorenza Romani, Maia De Luca, Sara Chiurchiù, Costanza Tripiciano, Stefania Mercadante, Clementien L Vermont, Henriëtte A Moll, Dorine M Borensztajn, Nienke N Hagedoorn, Chantal Tan, Joany Zachariasse, W Dik, Ching-Fen Shen, Dace Zavadska, Sniedze Laivacuma, Aleksandra Rudzate, Diana Stoldere, Arta Barzdina, Elza Barzdina, Monta Madelane, Dagne Gravele, Dace Svilz, Romain Basmaci, Noémie Lachaume, Pauline Bories, RajaBen Tkhayat, Laura Chériaux, Juraté Davoust, Kim-Thanh Ong, Marie Cotillon, Thibault de Groc, Sébastien Le, Nathalie Vergnault, Hélène Sée, Laure Cohen, Alice de Tugny, Nevena Danekova, Marine Mommert-Tripon, Karen Brengel-Pesce, Marko Pokorn, Mojca Kolnik, Tadej Avčin, Tanja Avramoska, Natalija Bahovec, Petra Bogovič, Lidija Kitanovski, Mirijam Nahtigal, Lea Papst, Tina Plankar Srovin, Franc Strle, Katarina Vincek, Michiel van der Flier, Wim J E Tissing, Roelie M Wösten-van Asperen, Sebastiaan J Vastert, Daniel C Vijlbrief, Louis J Bont, Coco R Beudeker, Philipp Agyeman, Luregn Schlapbach, Christoph Aebi, Mariama Usman, Stefanie Schlüchter, Verena Wyss, Nina Schöbi, Elisa Zimmermann, Marion Meier, Kathrin Weber, Colin Fink, Marie Voice, Leo Calvo-Bado, Michael Steele, Jennifer Holden, Andrew Taylor, Ronan Calvez, Catherine Davies, Benjamin Evans, Jake Stevens, Peter Matthews, Kyle Billing, Werner Zenz, Alexander Binder, Benno Kohlmaier, Daniela S Kohlfürst, Nina A Schweintzger, Christoph Zurl, Susanne Hösele, Manuel Leitner, Lena Pölz, Alexandra Rusu, Glorija Rajic, Bianca Stoiser, Martina Strempfl, Manfred G Sagmeister, Sebastian Bauchinger, Martin Benesch, Astrid Ceolotto, Ernst Eber, Siegfried Gallistl, Harald Haidl, Almuthe Hauer, Christa Hude, Andreas Kapper, Markus Keldorfer, Sabine Löffler, Tobias Niedrist, Heidemarie Pilch, Andreas Pfleger, Klaus Pfurtscheller, Siegfried Rödl, Andrea Skrabl-Baumgartner, Volker Strenger, Elmar Wallner, Maike K Tauchert, Shunmay Yeung, Manuel Dewez, David Bath, Elizabeth Fitchett, Fiona Cresswell, Effua Usuf, Kalifa Bojang, Anna Roca, Isatou Sarr, Momodou Saidykhan, Ebrahim Ndure, Ulrich von Both, Laura Kolberg, Patricia Schmied, Ioanna Mavridi, Irene Alba-Alejandre, Nikolaus Haas, Esther Maier, Sabrina Juranek, Tobias Feuchtinger, Katharina Danhauser, Matthias Griese, Matthias Kappler, Eberhard Lurz, Sebastian Schroepf, Florian Hoffmann, Karl Reiter, Carola Schoen, Luregn J Schlapbach, Eric Giannoni, Martin Stocker, Klara M Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Giancarlo Natalucci, Christa Relly, Christoph Berger, Thomas Riedel
Journal: JAMA Network Open (2023)

Importance Cardiac dysfunction and myocarditis have emerged as serious complications of multisystem inflammatory syndrome in children (MIS-C) and vaccines against SARS-CoV-2. Understanding the role of autoantibodies in these conditions is essential for guiding MIS-C management and vaccination strategies in children. Objective To investigate the presence of anticardiac autoantibodies in MIS-C or COVID-19 vaccine-induced myocarditis. Design, Setting, and Participants This diagnostic study included children with acute MIS-C or acute vaccine myocarditis, adults with myocarditis or inflammatory cardiomyopathy, healthy children prior to the COVID-19 pandemic, and healthy COVID-19 vaccinated adults. Participants were recruited into research studies in the US, United Kingdom, and Austria starting January 2021. Immunoglobulin G (IgG), IgM, and IgA anticardiac autoantibodies were identified with immunofluorescence staining of left ventricular myocardial tissue from 2 human donors treated with sera from patients and controls. Secondary antibodies were fluorescein isothiocyanate–conjugated antihuman IgG, IgM, and IgA. Images were taken for detection of specific IgG, IgM, and IgA deposits and measurement of fluorescein isothiocyanate fluorescence intensity. Data were analyzed through March 10, 2023. Main Outcomes and Measures IgG, IgM and IgA antibody binding to cardiac tissue. Results By cohort, there were a total of 10 children with MIS-C (median [IQR] age, 10 [13-14] years; 6 male), 10 with vaccine myocarditis (median age, 15 [14-16] years; 10 male), 8 adults with myocarditis or inflammatory cardiomyopathy (median age, 55 [46-63] years; 6 male), 10 healthy pediatric controls (median age, 8 [13-14] years; 5 male), and 10 healthy vaccinated adults (all older than 21 years, 5 male). No antibody binding above background was observed in human cardiac tissue treated with sera from pediatric patients with MIS-C or vaccine myocarditis. One of the 8 adult patients with myocarditis or cardiomyopathy had positive IgG staining with raised fluorescence intensity (median [IQR] intensity, 11 060 [10 223-11 858] AU). There were no significant differences in median fluorescence intensity in all other patient cohorts compared with controls for IgG (MIS-C, 6033 [5834-6756] AU; vaccine myocarditis, 6392 [5710-6836] AU; adult myocarditis or inflammatory cardiomyopathy, 5688 [5277-5990] AU; healthy pediatric controls, 6235 [5924-6708] AU; healthy vaccinated adults, 7000 [6423-7739] AU), IgM (MIS-C, 3354 [3110-4043] AU; vaccine myocarditis, 3843 [3288-4748] AU; healthy pediatric controls, 3436 [3313-4237] AU; healthy vaccinated adults, 3543 [2997-4607] AU) and IgA (MIS-C, 3559 [2788-4466] AU; vaccine myocarditis, 4389 [2393-4780] AU; healthy pediatric controls, 3436 [2425-4077] AU; healthy vaccinated adults, 4561 [3164-6309] AU). Conclusions and Relevance This etiological diagnostic study found no evidence of antibodies from MIS-C and COVID-19 vaccine myocarditis serum binding cardiac tissue, suggesting that the cardiac pathology in both conditions is unlikely to be driven by direct anticardiac antibody–mediated mechanisms.